Please use this identifier to cite or link to this item:
10.3390/cancers15010238
Title: | HIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection : DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cells |
Authors: | Petkov, Stefan Kilpeläinen, Athina Bayurova, Ekaterina Latanova, Anastasia Mezale, Dzeina Fridrihsone, Ilse Starodubova, Elizaveta Jansons, Juris Dudorova, Alesja Gordeychuk, Ilya Wahren, Britta Isaguliants, Maria Research Department |
Keywords: | CD8+ T-cell response;DNA immunogen;drug resistance;HIV-1;HIV-1-protein-expressing tumors;mammary gland adenocarcinoma 4T1luc2 cells;metastatic activity;protease;protection from tumor challenge;tumor growth;3.1 Basic medicine;3.2 Clinical medicine;1.1. Scientific article indexed in Web of Science and/or Scopus database;Oncology;Cancer Research;SDG 3 - Good Health and Well-being |
Issue Date: | Jan-2023 |
Citation: | Petkov , S , Kilpeläinen , A , Bayurova , E , Latanova , A , Mezale , D , Fridrihsone , I , Starodubova , E , Jansons , J , Dudorova , A , Gordeychuk , I , Wahren , B & Isaguliants , M 2023 , ' HIV-1 Protease as DNA Immunogen against Drug Resistance in HIV-1 Infection : DNA Immunization with Drug Resistant HIV-1 Protease Protects Mice from Challenge with Protease-Expressing Cells ' , Cancers , vol. 15 , no. 1 , 238 , pp. 1-45 . https://doi.org/10.3390/cancers15010238 |
Abstract: | DNA immunization with HIV-1 protease (PR) is advanced for immunotherapy of HIV-1 infection to reduce the number of infected cells producing drug-resistant virus. A consensus PR of the HIV-1 FSU_A strain was designed, expression-optimized, inactivated (D25N), and supplemented with drug resistance (DR) mutations M46I, I54V, and V82A common for FSU_A. PR variants with D25N/M46I/I54V (PR_Ai2mut) and with D25N/M46I/I54V/V82A (PR_Ai3mut) were cloned into the DNA vaccine vector pVAX1, and PR_Ai3mut, into a lentiviral vector for the transduction of murine mammary adenocarcinoma cells expressing luciferase 4T1luc2. BALB/c mice were DNA-immunized by intradermal injections of PR_Ai, PR_Ai2mut, PR_Ai3mut, vector pVAX1, or PBS with electroporation. All PR variants induced specific CD8+ T-cell responses revealed after splenocyte stimulation with PR-derived peptides. Splenocytes of mice DNA-immunized with PR_Ai and PR_Ai2mut were not activated by peptides carrying V82A, whereas splenocytes of PR_Ai3mut-immunized mice recognized both peptides with and without V82A mutation. Mutations M46I and I54V were immunologically silent. In the challenge study, DNA immunization with PR_Ai3mut protected mice from the outgrowth of subcutaneously implanted adenocarcinoma 4T1luc2 cells expressing PR_Ai3mut; a tumor was formed only in 1/10 implantation sites and no metastases were detected. Immunizations with other PR variants were not protective; all mice formed tumors and multiple metastasis in the lungs, liver, and spleen. CD8+ cells of PR_Ai3mut DNA-immunized mice exhibited strong IFN-γ/IL-2 responses against PR peptides, while the splenocytes of mice in other groups were nonresponsive. Thus, immunization with a DNA plasmid encoding inactive HIV-1 protease with DR mutations suppressed the growth and metastatic activity of tumor cells expressing PR identical to the one encoded by the immunogen. This demonstrates the capacity of T-cell response induced by DNA immunization to recognize single DR mutations, and supports the concept of the development of immunotherapies against drug resistance in HIV-1 infection. It also suggests that HIV-1-infected patients developing drug resistance may have a reduced natural immune response against DR HIV-1 mutations causing an immune escape. |
Description: | Publisher Copyright: © 2022 by the authors. |
DOI: | 10.3390/cancers15010238 |
ISSN: | 2072-6694 |
Appears in Collections: | Research outputs from Pure / Zinātniskās darbības rezultāti no ZDIS Pure |
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HIV-1_Protease_as_DNA_Immunogen_against_Drug_Resistance.pdf | 8.06 MB | Adobe PDF | View/Open |
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